BR112020018738A2 - PROCESS FOR THE PREPARATION OF (4S) -4- (4-CYANO-2-METOXYphenyl) -5-ETOXY-2,8-DIMETHYL-1,4-DIHYDRO-1,6-NAFTIRIDIN-3-CARBOXAMIDE THROUGH DISSOCIATION OF RACEMATE THROUGH DIASTEREOMERIC TARTARIC ACID ESTERS - Google Patents

Abstract

process for the preparation of (4s) - 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyr-din-3-carbox-amide through the dissociation of racemate by means of diastereomeric tartaric acid esters. the present invention relates to a new and improved process for the preparation of (4s) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1, 6-naphthyridin-3-carboxamide of the formula (i), as well as the preparation of the enantiomer (ia) by dissociation of the racemate with substituted chiral tartaric acid esters of the free formulas (iiia) and (iiib), being that air represents a substituted or unsubstituted aromatic or heteroaromatic radical.

Description

Invention Patent Specification Report for "PROCESS FOR THE PREPARATION OF (4S) -4- (4-CYAN-2-METOXYphenyl) -5-ETOXY-2,8-DIMETHYL-1,4-DIHYDRO-1,6 -NAFTIRI- DIN-3-CARBOX-AMIDA THROUGH RACE-MATO DISSOCIATION THROUGH DIASTE-REOMERIC TARTARIC ACID ESTERS. "

[001] The present invention relates to a new and improved process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4 -dihydro-1,6-naphthyridin-3-carboxamide of the formula (I) as well as the preparation of the enantiomer (Ia) through a dissolution of racemate with substituted chiral tartaric acid esters of the general formulas (IIIa) and (IIIb)

(IIIa) (IIIb) where Ar represents a substituted or unsubstituted aromatic radical or heteroaromatic radicals.

[002] Finerenone (I) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as an agent for the prophylaxis and / or treatment of cardiovascular and renal diseases, such as, for example, heart failure and diabetic nephropathies .

[003] The radical of formula (I) and its preparation process are described in WO 2008/104306 and ChemMedChem 2012, 7, 1385, as well as in WO 2016/016287 A1. To obtain the compound of formula (I), the racemic mixture of amides (II) (II) (R, S-II) must be separated at the antipodes, since only the antipode of formula (I) is active.

[004] In the synthesis of the published research (WO 2008/104306), a specially synthesized chiral phase (own preparation) was used for this purpose, which, as a chiral selector, contained poly (N-methacryloyl-

D-leucin-dicyclopropylmethylamide. It was found that the separation can also be carried out in a commercially accessible phase. Here, this is the Chiralpak AS-V phase, 20 µm. As a eluent, a 60:40 methanol / acetonitrile mixture was used. Here, the chromatography can be performed on a commercially available chromatography column, preferably, however, techniques known to the specialist are used, such as simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901).

1) chiral HPLC 2) racemic EtOH crystallization

[005] Although the SMB separation provides relatively good performance and optical purity, the acquisition costs and the operation of such an installation under GMP conditions, represent a major challenge and are associated with high costs. The chiral phase used is also very expensive and has only a limited useful life and must be replaced frequently in continuous production. For production engineering reasons, this is not ideal, unless there is a second installation to ensure continuous operation, which is also associated with additional costs. In addition, mainly in products, which are manufactured on a ton scale, solvent recovery is the determining step in time and requires the acquisition of gigantic descending film evaporators and is associated with the consumption of huge amounts of energy.

[006] Therefore, the task consisted of looking for alternatives for the separation of the enantiomer mixture, which are significantly more economical and can be carried out with conventional plant-plant equipment (stirring boiler / isolation devices) . Such facilities are traditionally included in the standard equipment of pharmaceutical production units and do not require any additional investments. The qualification and validation of batch processes is also much simpler than in chromatographic processes, which is an additional advantage.

[007] Numerous attempts have been made to develop a separation with the common classic methods for the dissociation of the racmate (variation of chiral organic acid and solvent), as shown in Table 1: Table 1: Hydrogen phosphate solvent acid of (S) - (+) - 1,1-binaftymethanol 2,2-diyl acid (-) - quinic acid ethanol (-) - O, O'-diacetyl-L-tartaric acid 1 - propanol (-) -O, O'-dipivaloyl-L-tartaric acid 2-propanol (+) - 3-bromochanfor-10-sulfonic acid 1-butanol (+) - 4-chloro-tartranilic isobutanol (+) - 4-nitrotartranilic 1- pentanol acid (+) - camphoric acid cyclohexanol (+) - O-acetyl-L-mandelic benzyl alcohol (1R) - (-) - camphor-10-sulfonic acid acetone (1S) - (-) - camphoric ethylene glycol ( 2R, 3R) - (+) - tartaric chlorobenzene acid (R) - (+) - alpha-methoxy-alpha-dichloromethane trifluoromethylphenylacetic acid (S) - (-) - bromopropionic ethyl acetate (S) - (-) - 2-chloropropionic dimethylacetamide acid (S) - (+) - citramálico THF acid (S) - (+) - mandelico toluene mixture tri Ac-toluene acid / ethyl acetate 95: 5 malic acid (malicacide) toluene / ethyl acetate 90:10 toluene / ethyl acetate 80:20 mono-acid D - (+) - HPP toluene / acetate ethyl 50:50 L-glutamic acid toluene / ethanol 95: 5 L-lactic acid methanol / water 90:10 methoxyacetic acid methanol / water 80:20 N- (3,5-dinitrobenzoyl) - (R) - (-) - 2- methanol / water 50:50 phenylglycine N-acetyl-L-leucine ethyl acetate / MeOH 90:10 N-acetyl-L-phenylalanine ethanol / water 90:10 N-Ac-proline-OH ethanol / water 85:15 naproxen ethanol / water 80:20 phenol ethanol / water 75:25 ethanol / water 70:30 ethanol / water 50:50 methanol / water 90:10 methanol / water 80:20 methanol / water 50:50 1-propanol / water 80 : 20 isopropanol / water 80:20 1-butanol / water 90:10 2-butanol / water 80:20 2-butanol / water 90:10 1-pentanol / water 90:10 cyclohexanol / water 90:10 benzyl alcohol / water 90:10 ethylene glycol / water 80:20

[008] Among others, experiments were also carried out with the classic acid dissociation reagent (+) - tartaric.

[009] However, in all cases no salt formation was observed, instead, only the racemate always precipitates without salt from the solution. This essentially corresponds to the expert's expectations, which could have been deviated from the pKs value of the molecule (II), that a classic dissociation of the racemate through the formation of diastereomeric salt with organic acids should not be possible, since the value measured pKs (for the base) is 4.3 and almost completely excludes salinization, so that only salt formation using very strong inorganic or organic mineral acids, such as, for example, chiral sulfonic acids or phosphonic acids. According to the literature, such as, for example, “Handbook of Pharmaceutical Salts - Properties, Selection and Use; by P. Heinrich Stahl, Camille G. Wermuth (Eds.); Wiley-VCH, page 166 ”, the difference in the pK value should be at least 3 pK units, in order to enable stable salt formation. This is actually found when, for example, the cyclic phosphoric acid ester clociphos shown below: clociphos

[0010] In the reaction with 3 equivalents of this cyclic phosphoric acid ester with the racemate (II) a diastereomeric salt is obtained, in which (I) is present with an excess of 44% e.e. enantiomers

[0011] All efforts to bring excess enantiomers towards> 99% have not been successful; in addition, clociphos was not commercially available in larger quantities, so other alternatives were sought.

[0012] In the reaction with alkyl substituted tartaric acid derivatives, such as, for example, (-) - O, O'-dipivaloyl-L-tartaric acid or (-) - O, O'-diacetyl-L- tartaric acid, no salt formation was observed.

[0013] In the other study on the topic, it was surprisingly found that aromatically or heteroaromatically substituted derivatives of tartaric acid are highly suitable for forming “diastereomeric salts” from the racemate (II).

[0014] The purpose of this application is therefore to dissociate the racemate from (II) (II) (R, S-II) in (Ia) and / or (I)

(Ia) (I) with substituted chiral tartaric acid esters of the general formulas (IIIa) or (IIIb) (IIIa) (IIIb) where Ar represents an unsubstituted or substituted aromatic radical or heteroaromatic radical.

[0015] Another objective concerns the process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridin-3-carbox-amide of formula (I) (I) by dissociating the racemate from (II)

(R, S-II) with a substituted chiral tartaric acid ester of formula (IIIa) (IIIa) where Ar represents an unsubstituted or substituted aromatic radical or heteroaromatic radical.

[0016] The term "substituted" means that one or more hydrogen atoms is / are substituted / s in the respective atom or in the respective group by a selection from the indicated group, with the proviso, that the normal valence of the respective atom is not exceeded under these conditions. Combinations of substituents and / or variables are permitted.

[0017] The term "unsubstituted" means that no hydrogen atom has been replaced.

[0018] In the case of the heteroaryl group or the heteroaromatic radical it may be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or te-

trazolila; or from a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or from a tricyclic heteroaryl group, such as, for example, carbazolyl, acydinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indiol, isoindolyl, indolizinyl or purinyl; or from a 10-membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

[0019] In particular, in the case of the heteroaryl group, it is a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.

[0020] The aryl group in the sense of the present application is, in particular, a phenyl group.

[0021] As substituents in the sense of the present invention, halogen, C1-C6-alkyl, C1-C6-alkoxy, nitrile, a nitro group, cyano group, CF3 group or amide group are included, such as, for example , NHCOR, in which R can represent methyl, ethyl or phenyl or a –NRCOR group, in which it has the meaning mentioned above or a CONHR group, in which R has the meaning mentioned above or a CONRR 'group, in which R 'has the same meaning as R, as defined above or cyclic amides, such as a –COmorpholine radical, –Copiperidine radical.

[0022] The term halogen means a fluorine, chlorine, bromine or iodine atom, in particular, a fluorine, chlorine or bromine atom.

[0023] The term "C1-C6-alkyl" represents a saturated monovalent hydrocarbon group, in a straight or branched chain with 1, 2, 3, 4, 5 or 6 carbon atoms, for example, a methyl, ethyl group , propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1 -dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-

methylpentyl, 4-methylpentyl, 1-ethylabutyl, 2-ethylabutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl or an isomer of it. The group has, in particular, 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), for example, a methyl, ethyl, propyl, isopropyl, butylal, sec-butyl, isobutyl group tyl, tert-butyl, in particular 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), for example, a methyl, ethyl, n-propyl or isopropyl group.

[0024] The term "C1-C6-alkoxy" represents a monovalent saturated, straight or branched chain formula (C1-C6-alkyl) -O-, in which the term "C1-C6-alkyl" is defined as as above, for example, a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy or an isomer thereof.

[0025] Preferably, Ar represents: in which R1, R2, R3, R4, R5 respectively represent a hydrogen atom or an alkyl radical, such as, for example, methyl, ethyl, propyl or a halogen atom, such such as, for example, fluorine, chlorine, bromine or iodine or an ether group, such as, for example, O-methyl, O-ethyl, O-phenyl or a nitro group, cyano group, CF3 group or a group amide po, such as, for example, NHCOR, in which R can represent methyl, ethyl or phenyl or a group -NRCOR, in which R has the aforementioned meaning or a CONHR group, in which R has the meaning mentioned above or a CONRR 'group, in which R' has the same meaning as R, as defined above or represents cyclic amines, such as, a radical -Comorpholine, -Copiperidine. Replacement samples can be very different, so theoretically

Up to 5 different substituents may be possible, as a rule, however, monosubstituted Ar radicals are preferred. However, Ar can also be a substituted heteroaromatic radical, such as preferably pyridine or pyrazine. It may also be a polycyclic aromatic hydrocarbon, such as, for example, substituted naphthalene, anthracene or quinoline.

[0026] As Ar are particularly preferred: where * represents the point of attachment.

[0027] Very particularly preferred Ar radicals are: where * represents the point of attachment.

[0028] Of these, the unsubstituted ring (phenyl) is particularly preferred.

[0029] The preparation of the tartaric acid ester is known from the literature, as, for example, it is described in Organic Synthesis, Coll. Vol. 9, page 722 (1998); 72, page 86 (1995), as well as in Chirality 2011 (23), 3, page 228.

[0030] Likewise, another objective refers to the daily salts

tereomeric according to the formulas

(IVa)

(IV-b)

(IV-c) or

(IV-d) in which Ar represents an unsubstituted or substituted aromatic or heteroaromatic radical and has the meaning indicated above.

[0031] Particularly preferred are diastereomeric salts, in which Ar represents phenyl.

[0032] Whether, in this case, it is really a classic diastereomeric salt or a 1: 1 molecular complex stabilized through hydrogen bonding, it is clearly not predictable. What is certain is that these aggregates of 1: 1 molecules are very stable and behave like classic diastereomeric salts and can be isolated, so we use the name diastereomeric salt below. For the preparation of diastereomeric salts, derivatives of tartaric acid of the general formula (IIIa) and (IIIb) are used: (IIIa) (IIIb) in which Ar represents substituted or unsubstituted aromatic or heteroaromatic radicals.

[0033] The preparation of diastereomeric salts is carried out as

follows:

racemisch = racemic

[0034] The reaction of the racemic mixture (II) with a derivative of tartaric acid of the general formula (IIIa) or (IIIb) results in the 4 possibilities of formation of the diastereomeric salt (IV a-d). Surprisingly, there is, in this sense, a certain preference, that, for example, when rac- (II) is reacted with a derivative of tartaric acid of the general formula (IIIa), in most In these cases, the diastereomeric salt of the general formula (IVa) is obtained, the antipode of the S configuration preferably forming the salt.

The diastereomeric salt (IVa) precipitates almost quantitatively from the solution, from which it can be isolated, then, for example, through filtration, the antipode with the R configuration remaining in solution.

In a very similar way, the reflected image of the salt of the general formula (IVb) is prepared, in which the racemate (II) is reacted with the tartaric acid derivative of the general formula (IIIb), with the antipode of the R configuration. preferably forms the salt.

The precipitated diastereomeric salts can

they can be separated almost quantitatively, and here the S antigen remains in solution.

[0035] Through the stoichiometric ratio from (II) to (IIIa), respectively (IIIb), as well as through the selection of the solvent, the yield and the enantiomeric unit can be optimized.

[0036] Since finerenone (I) has the S configuration, tartaric acid derivatives with S, S configuration are preferably used for the dissociation of the racemate, since in this case, the diastereomeric salt of the antipode is preferably formed S.

[0037] 0.4 to 1.2 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for the dissociation of the racemate, preferably, however, 0.4 to 0.7 equivalent, so particularly preferred, however, 0.45 to 0.6 equivalent, but very particularly preferred, 0.50-0.55 equivalent.

[0038] The formation of the diastereomeric salt occurs in mixtures of solvents, which consist of water and organic solvents miscible with water.

[0039] As organic solvents in the order required, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone are suitable; but preferably ethanol is used. Solvents can also be used in the commercially available denatured form, such as the denaturing agents used in ethanol, for example, toluene, methyl ethyl ketone, thiophene, hexane, which, for technical cost reasons, have great advantages therefore, in particular, the spirit is suitable, in particular, for use on an industrial scale, which in the sense of the order consists of ethanol, which can be optionally denatured with toluene or with methyl ethyl ketone. In the sense of the present application, therefore, if afterwards ethanol is mentioned as a solvent, it should be understood, in addition to pure ethanol, in particular

ticular, also spirit for use on an industrial scale, in the sense of the definition mentioned above. In addition, the following solvents were also used: ethyl acetate / methanol 90:10; methanol / water 80:20; ethanol / water 90:10; 85:15 ethanol / water; 80:20 ethanol / water; 75:25 ethanol / water; 70:30 ethanol / water; dichloromethane; 1- 80:20 propanol / water; 1-pentanol; 1-pentanol / water 90:10; isopropanol; isopropanol / water 80:20; isobutanol / water 90:10; isobutanol / water 80:20; cyclohexanol / water 90:10; benzyl alcohol / water 90:10; ethylene glycol; ethylene glycol / water 80:20.

[0040] Preferably, the dissociation of the racemate is carried out in an ethanol / water mixture, the mixtures (vol / vol) being in the ethanol: water range from 1: 1 to 6: 1. But preferably a mixture of ethanol: water from 4: 1 to 3: 1 is used. Particularly preferred, a 3: 1 mixture of ethanol: water is used. The mixture can be prepared in advance or it can be produced in situ, after having previously introduced all the components into a bowl. The solvent mixture can be used in excess of 10 to 40 times based on the racemate (II), for example, for 1 kg of racemate 10 liters to 40 liters of solvent mixture are used. An excess of 10 to 20 times, in particular, 13 to 16 times is preferred - in particular an excess of 14 to 15 times is preferred.

[0041] In general, the dissociation of the racemate occurs when initially all the components are previously introduced into the solvent mixture at room temperature, then the mixture is heated to 60 to 80oC, but preferably to 75oC and stirred for 2 to 10 hours, preferably 3 to 4 hours at 75oC and then within 3 to 10 hours, preferably within 4 to 5 hours it is cooled to room temperature (about 20 to 23oC (by means of a ramp) Then allow to cool for 2 to 24 hours, preferably 5 to 18 hours, most particularly preferably 12 to 24 hours.

16 hours at room temperature. The dissociation of the racemate occurs preferably at a temperature of 75oC.

[0042] Then, the precipitated diastereomeric salt (IVa), (IVb), (IVc) and / or (IVd) is isolated.

[0043] Isolation takes place by methods known to the specialist, such as, for example, through filtration or through a centrifuge. The filter cake thus obtained can be washed again one or more times with a solvent or a mixture of solvents. Then, vacuum drying occurs, preferably <100 mbar at elevated temperature (50 to 80 ° C, preferably at 50 ° C). The use of carrier gas has proven to be advantageous in some cases.

[0044] With the operating method described above, chemically very pure diastereomeric salts can be prepared. The excess enantiomer of diastereomeric salts is, as a rule,> 97% e.e. (see examples).

[0045] Diastereomeric salts need not necessarily be dry, but yes, they can also be used wet in the subsequent step of the process.

[0046] The process steps, in addition to the procedures mentioned above, can also be combined or changed in order, as shown in the following table 2:

Table 2 1st stage 2nd stage 3rd stage 4th stage 5th stage introduction pre-addition of heating addition of racema-ethanol water to (II) and diaryl-tartaric acid (IIIa or b) introduction pre-addition of addition of racema-ethanol diary acid-water to (II) tartaric (IIIa or b) addition pre-addition of racema-diary acid-ethanol water to (II) addition ) tartaric (IIIa or b) introduction pre-addition of addition of warming acid addition of ethanol racemate (II) aryl-tartaric water (IIIa or b) introduction pre-addition of addition of ethanol via di acid - racemate water (II) aryl-tartaric (IIIa or b) introduction pre-addition of heating via the racema- mixture of to (II) and ethanol-diaryl-tartaric water (IIIa or b) introduction pre-addition of the addition of addition of racema warming-mixture of diaryl acid-ethanol to (II) ethanol-tartaric water (IIIa or b)

1st stage 2nd stage 3rd stage 4th stage 5th stage introduction pre-addition of addition of racemate acid addition (II) mixture aryl-tartaric acid ethanol-water (IIIa or b) introduction pre-addition of addition of heating of the racemate mixture diary acid of ethanol-water (II) tartaric (IIIa or b) introduction of pre-addition of heating addition of the mixture diaryl acid racemate (II) to of ethanol-tartaric water (IIIa or b) introduction pre-addition of addition of racemate ethanol warming water water diary (II) tartaric acid (IIIa or b) introduction of addition of racemate ethanol water addition tartaric acid (II) tartaric (IIIa or b) introduction pre-addition of addition of ethanol heating diary acid-water racemate mentary (II) (IIIa or b) introduction of addition pre-addition of addition water heating diaryl-ethanol tartaric racemate (II) (IIIa or b)

[0047] Depending on the type of installations in the pilot installation or in production, one or the other variant can be advantageous.

[0048] In the next step, the diastereomeric salt is treated with a base and the solvent is removed. The removal of the solvent occurs according to methods known to the skilled person, for example, by distillation. For the preparation of chiral compounds (I) and (Ia), the diastereomeric salt of the general formula (IVa), (IVb), (IVc) or (IVd) must be treated with a base, in this case, the target molecule (I ) or (Ia), after distilling the organic solvent, precipitates from the solution, is isolated - for example, through filtration and post-wash and the respective tartaric acid ester according to formula (IIIa) or (IIIb ) remains in saline form in solution.

(IVa) (I) (IVb) (Ia) (IVc) (I)

(IVd) (I)

[0049] As bases in the sense of the present invention, inorganic and organic bases are suitable. In the case of inorganic bases, ammonia, lye, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate can be used. sodium bonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate. Preferably, however, sodium phosphate or potassium phosphate is used. It is important to emphasize that inorganic bases can be used both in anhydrous form and also in the form of their hydrates, so, for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. As an organic base, aliphatic or aromatic bases can be used, such as, for example, triethylamine, imidazole, N-methylimidazole, Hünig's base, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU).

[0050] The release of the target compound (I) or (Ia) occurs in mixtures of water, water-miscible organic solvents, such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, but is preferably ethanol is used. The solvents can also be used in the commercially available denatured form, such as the denaturing agents used in ethanol, for example, toluene, methyl ethyl ketone, thiophene, hexane, preferably the brandy, which in the sense of order, consists of in ethanol, which can be optionally denatured with toluene or methyl ethyl ketone, which also brings great advantages for technical reasons of costs. It has been proven to be advantageous to use mixtures of water and ethanol, the mixtures (vol / vol) being in the range of ethanol: water from 1: 6 to 1: 3. But preferably an ethanol mixture is used: 1: 4 water. The mixture can be prepared in advance or produced in situ, after having previously introduced all the components in a bowl. 7 to 20 times of this mixture can be used based on the diastereomeric salt used (IVa or IVb or IVc or IVd), therefore, for example, 1 kg in 7 liters to 20 liters of this mixture. Preferably, 8 - 12 times of this mixture are used, particularly preferably, 9 - 11 times of this mixture are used, most particularly preferably, 10 times.

[0051] The release of the target compound (I) or (Ia) occurs in which the diastereomeric salt (IVa or IVb or IVc or IVd) is previously introduced in a solvent mixture at 0 to 80oC, preferably 20 to 50oC, then , by adding the organic or inorganic base (either in solid form or as a solution, preferably in water), a pH value of 6.9 to 9.5, preferably a pH value of 7.0 to 8, is adjusted, 0, particularly preferably, pH 7.5. The base can optionally be added very quickly (within a few minutes) or also very slowly (within several hours), such as, for example, in 5 minutes to 3 hours. A faster addition is preferred in any case, it is preferably added within 5 minutes to 1 hour. For this purpose, a pH meter installed in the reactor can be used, with which the adjustment is controlled and the base is added slowly. However, even from the beginning, it is possible to add a solid amount of base (solid or dissolved in a solvent) which, based on experimental values, ensures that the desired pH value range is preferably obtained. Such a procedure is particularly preferred in production. It has been proven to be advantageous if, after adjusting the pH value, the mixture is again stirred at 10 to 80oC, preferably at 20 to 60oC, preferably at 40-60oC. In this case, the additional stirring period can be from 1 to 10 hours, preferably 2-5 hours, particularly preferably 3-4 hours. Then, it is allowed to cool to 15 to 25oC, for example, on a ramp and then it is stirred again for 1 to 64 hours (the 64 hours serve to demonstrate the robustness of the process, see example 3b), however, preferably, it is again stirred between 3 and 24 hours, however, as a rule, 10 to 20 hours is enough.

[0052] The isolation takes place according to methods known to the specialist, such as, for example, through filtration or through a centrifuge. The filter cake thus obtained can be washed again, one or more times with a solvent or mixture of solvents. Thereafter, vacuum drying occurs, preferably <100 mbar at elevated temperature (50 to 80 ° C, preferably 50 ° C). The use of carrier gas has proven to be advantageous in some cases.

[0053] However, it is also possible to dissolve the material obtained from the filter in ethanol or in mixtures of water with ethanol and then, after adjusting the amount of water / ethanol in the eluate, proceed immediately to the next step in the process (see below) . This procedure is preferred, in particular, on an industrial scale, since a drying step can be dispensed with.

[0054] With the operating mode described above, it is possible to prepare chemically very pure crude products. The enantiomeric excess of crude products (I) and (Ia) is, as a rule,> 96.5% e.e.

[0055] In the context of scaling up it has been demonstrated that the complete separation of the esters of tartaric acid (IIIa) and (IIIb) from crude products (I) and (Ia) technically cannot always be performed very simply and the content of these components is close to the specification limit.

Since the requirements for specification in the final active substance are very high (<0.1% (IIIa) in the final active substance), it has been proven to be advantageous in some cases to add another step in the process, which ensures that the content of esters of tartaric acid (IIIa) is reduced to less than 0.15%, preferably to less than 0.1% and, in particular, to less than 0.05% and the final active substance is reproducibly obtained as specifications.

The tartaric acid ester (IIIa) is little or almost not exhausted in the final crystallization to obtain the pure product, so that such a subsequent step of the process guarantees, so that a robust procedural mode of the whole process is ensured, in addition to moreover, one works almost at a loss.

This process step, which ensures that the compound (IIIa) is depleted to less than 0.15%, preferably less than 0.1% and, in particular, to less than 0.05% in the active substance, is , likewise, object of the present invention.

The process for reducing (IIIa) is carried out as follows.

For this purpose, the dry crude product or, advantageously, still wet from (I) or (Ia) is used. For this purpose, a base is used again.

For the removal of tartaric acid esters of the formula (IIIa) or (IIIb) inorganic and organic bases are used.

In the case of inorganic bases, ammonia, lye, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate can be used. sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate.

Preferably, however, sodium hydroxide, sodium phosphate or potassium phosphate is used.

Particularly preferably, sodium phosphate or potassium phosphate is used.

It is important to emphasize that inorganic bases can be used both in anhydrous form and also in the form of their hydrates, so, for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. As an organic base, aliphatic or aromatic bases can be used, such as, for example, triethylamine, imidazole, N-methylimidazole, Hünig's base, pyridine, DBU.

[0056] The depletion of (IIIa) or (IIIb) occurs in mixtures of water, water-miscible organic solvents, such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, however, it is preferably used ethanol. The solvents can also be used in the commercially available denatured form, such as the denaturing agents used in ethanol, for example, toluene, methyl ethyl ketone, thiophene, hexane, which brings great advantages for technical cost reasons. It has been proven to be advantageous to use mixtures of water and ethanol, the mixtures (vol / vol) being in the range of ethanol: water from 30: 10 to 10: 10. Preferably, however, a mixture of ethanol: 20: 10 water. The mixture can be previously prepared or produced in situ, after having previously introduced all the components in a bowl. The solvent mixture can be used in excess of 10 to 20 times, based on the diastereomeric salt IVa, IVb, IVc or IVd used, therefore, for example, 1 kg in 10 liters to 20 liters of this mixture. Preferably, 10 - 14 times of this mixture are used, particularly preferably, 11 - 12 times of this mixture are used.

[0057] The depletion of (IIIa) or (IIIb) occurs in such a way that it is previously introduced in a solvent mixture, as described above, at 40 to 80oC, preferably 50 to 70oC, then by adding the organic or inorganic base (either in solid form or as a solution, preferably in water) a pH value of 6.9 to 9.5, preferably a pH value of 7.5 to 9.0, is adjusted, particularly preferably, pH 8.5. The base can be optionally

added very quickly (within a few minutes) or very slowly (within several hours), such as, for example, in 1 minute up to 3 hours. A faster addition is preferred in any case, preferably it is dosed within 1 minute to 1 hour. For this purpose, a pH meter installed in the reactor can be used, with which the adjustment is controlled and the base is dosed slowly. However, it is also possible from the start to add a solid amount of base (solid or dissolved in a solvent) which, based on experimental values, ensures that the desired pH value range is preferably obtained. Such a procedure is most preferred in production. It has been proven to be advantageous if, after adjusting the pH value, the mixture is again stirred continuously at 40-80oC, preferably at 50-75oC, preferably at 60-70oC. In this case, the additional stirring period may be from 1 to 24 hours, preferably 2-10 hours, particularly preferably 2-4 hours. Then, the organic solvent is widely distilled, this can occur under normal pressure or more carefully, under reduced pressure. As soon as the organic solvent is widely distilled, it is allowed to cool to 15-25oC, for example, through a ramp and afterwards it can be stirred again for 1 to 64 hours (the 64 hours serve to demonstrate the robustness of the process, see example 3b), however, it is preferably stirred again between 1 and 24 hours, however, as a rule, it will only take 1-5 hours.

[0058] The isolation takes place according to methods known to the specialist, such as, for example, through filtration or through a centrifuge. The filter cake thus obtained can be washed again, one or more times with a solvent or a mixture of solvents. Then, vacuum drying occurs, preferably <100 mbar at elevated temperature (50 to 80oC, preferably at 50oC). The use of carrier gas has proven to be advantageous in some

SOS.

[0059] It is also possible, before distilling the solvent, to readjust the pH value with an organic acid, such as, for example, formic acid, citric acid, acetic acid or inorganic acid, such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid or with an acidic salt, such as, for example, sodium dihydrogen phosphate, potassium hydrogen sulfate or sodium hydrogen sulfate to pH 5 - 7 and then continue as described above.

[0060] With the operation method described above, it is possible to prepare chemically very pure crude products. The enantiomeric excess of the crude products (I) and (Ia) is, as a rule,> 97% e.e. The content of (IIIa) or (IIIb) is reduced to less than 0.15%, preferably less than 0.1% and, in particular, less than 0.05%.

[0061] It has been proven to be advantageous to further subject a crude product thus obtained from formula (I) or (Ia) to further crystallization and to improve both chemical purity and mainly optics. For this purpose, a final crystallization process was developed: for this purpose, for technical reasons of GPM, the crude product (I) or (Ia) is dissolved in ethanol (optionally through heating) and then , subjected to particulate filtration, brandy or ethanol denatured with toluene is preferably used. In some cases, depending on the technical equipment, crystallization can also be carried out under pressure, at a high temperature (advantage: less solvent), however, it can also be recrystallized in aqueous ethanol solutions (under pressure or at normal pressure). After the mixture is concentrated at normal pressure or reduced pressure to about 1/3 to 1/6, preferably 1/4 to 1/5, in this case, the product crystallizes. In some cases, for example, when large volumes must be distilled over long periods, it has been proven to be advantageous to distill under reduced pressure, maintaining the temperature

low internal rature, in order to avoid decomposition and the formation of by-products. After distillation is complete, the mixture is at 0oC and then the crystals are isolated and vacuum dried at 40 to 50oC. Yields are, as a rule,> 88% of theory. The chemical purity obtained and the content correspond to the criteria for commercial products according to the ICH guideline. The residual solvent, in this case, ethanol, as a rule in technical preparations, is <0.05%. The optical purity is >> 99% e.e.

[0062] As a particularly preferred process, in particular, for industrial scale ralization, (+) - dibenzoyl-tartaric acid (III) is used, it can be used both in anhydrous form, as well as hydrate : brandy / racemic water

[0063] The dissociation of the racemate is preferably carried out in a spirit-water mixture. The subsequent release of finonone, crude spirit / water occurs preferably in a mixture of spirit-water using sodium phosphate as a base. In cases where re-processing is necessary, if the proportion of (+) - dibenzoyl-tartaric acid (II) is> 0.15% brandy / water, reprocessing preferably takes place in a mixture of water-water using sodium phosphate as a base. Final crystallization to obtain pure finerenone preferably takes place in water as a solvent. In this case, a purity of 0.15%, preferably 0.1%, is particularly preferred, with 0.05% of purities.

[0064] It is also possible to isolate the target enantiomer from the mother liquor. Here, initially the corresponding diastereomeric salt (IVa), (IVb), (IVc) or (IVd) is prepared either from (I) or (Ia), then it is isolated through filtration and then mother liquor, which then contains the respective antipode, is adjusted by adding a base, such as, for example, ammonia, lye, lithium hydroxide, potassium hydroxide, carbonate ammonium, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate

sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, preferably sodium hydroxide, sodium phosphate and potassium phosphate, particularly preferably sodium phosphate and potassium phosphate, for a pH value for pH> 7, preferably pH 7.5. Then, the organic solvent, preferably ethanol, is distilled either at normal pressure or more carefully, under reduced pressure, in this case, the corresponding antipode precipitates. The product is filtered, washed with water or a water / solvent mixture and dried. A corresponding final crystallization from brandy, such as, for example, described in example 1c, provides compounds (I) and (Ia) in correspondingly pure form.

(I) in mother liquor

[0065] Another objective of the present application is therefore to obtain finerenones (I) with a content of dibenzoiltartaric acid <0.15% by the fact that the racemate (II)

(R, S-II) (II) is reacted with dibenzoyltartaric acid of formula (III)

in a spirit / water mixture to form the diastereomeric salt (VI)

and then the finerenones (I)

(I) are released using sodium phosphate, in the same way, in a mixture of brandy / water and then it is reacted again with sodium phosphate in a mixture of brandy / water and then the finins are crystallized with a content of dibenzoyltartaric acid <0.15%; in a particularly preferred embodiment, finerenones are obtained with a dibenzoyltartaric acid content <0.1%, in particular, preferably with a dibenzoyltartaric acid content of less than 0.05%. Experimental part Abbreviations and acronyms: EtOH ethanol DB tartaric acid dibenzoyltartaric acid DMSO dimethylsulfoxide d.th. theory (in case of performance) HPLC high performance liquid chromatography, high performance 1H-NMR nuclear resonance spectrometry 1H TI internal temperature MS mass spectrometry TR retention time TRR relative retention time TFA trifluoroacetic acid TM jacket temperature

XRPD X-ray diffraction (powder) (powder diffractometry) spirit denatured ethanol with 2% toluene

EXAMPLES

[0066] The following table 3 reproduces the structures of the compounds recovered on HPLC. The allocation of HPLC retention times is shown below. Table 3 finerenone (I) impurity A impurity B impurity C (unknown structure, always significant below 0.1%)

impurity D impurity E impurity F impurity G impurity H impurity I impurity J impurity K impurity N (III)

1) Analytical method to test the impurity content and the enantiomeric purity in the step of the di-benzoyl-tartaric acid content and imp (TR) (min) TRR organic contents di-benzoyl-tartaric acid about 11.1 1.00 mono-benzoyl-tartaric acid about 5.1 0.46 benzoic acid about 7.6 0.69

Instrument: ultra high performance liquid chromatograph (with pressure range up to 1200 bar with thermostatic column oven and UV detector) Column: YMC Triart C8 length: 100 mm, internal diameter: 3.0 mm, grain size: 1 , 9 µm maximum pressure: 1000 bar Conditions: 20o C; 0.50 ml / min; 1.7 µl (10oC); 240 nm / 6 nm Eluting agent: A: 0.1% TFA in water; B: acetonitrile Gradient: time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 Enantiomeric purity: TR TRR acid (+) - di-benzoyl-tartaric 2.1 1.00 acid (-) - di-benzoyl-tartaric 3.9 1.86 Instrument: high performance liquid chromatograph with no. of thermostatic column and UV detector Column: Chiralpac IC length: 250 mm, internal diameter: 4.6 mm, grain size: 5.0 µm maximum pressure: 300 bar Conditions: 40oC; 2.0 ml / min 5 ml; 234 nm / 6 nm Eluting agent: A: heptane, B: 0.1% TFA in isocratic ethanol: A (%) 80: B (%) 20 2) Analytical method to test the impurity and purity content thiomeric in the diastereomeric salt stage TR (min) TRR Content and impurities finerenone (I) 6.2 1.00 organic impurity A 3.3 0.53 impurity B 3.7 0.60 impurity C 3.0 0.63 impurity D 4.4 0.70 impurity E 5.5 0.89 impurity F 6.8 1.10 impurity G 7.2 1.17 impurity H 7.7 1.25 impurity I 7.8 1.27 impurity J 8 , 4 1.36 impurity K 10.4 1.69 impurity N 11.1 1.80 Instrument: ultra high performance liquid chromatograph (with a pressure range of up to 1200 bar with thermostatic column oven and UV detector) Column: YMC Triart C8 length: 100 mm, internal diameter: 3.0 mm, grain size: 1.9 µm maximum pressure: 1000 bar Conditions: 20oC; 0.50 ml / min; 3.5 µl (10oC); 242 nm / 6 nm Eluting agent: A: 0.1% TFA in water: B: acetonitrile Gradient: time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35 , 0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 Enantiomeric purity: TR (min) TRR finerenone (I) 5.34 1.00 (Ia) 6.14 1.15 Equipment: high performance liquid chromatograph with thermostatic column shape and UV detector Column: Lux 3 µm i-cellulose-5 length: 150 mm, internal diameter: 4.6 mm, grain size: 3.0 µm pressure maximum: 300 bar Conditions: 40oC; 1.0 ml / min; 10 µl (20oC); 252 nm / 6 nm

Eluting agent: A: 20 mmol of ammonium acetate buffer pH 9.0 (1.54 g ammonium acetate in 1 liter of milli-Q water and ammonia adjusted to pH 9.0); B: Isocratic acetonitrile: A (%) 50: B (%) 50 3) Analytical method to test the impurity content and enantiomeric purity in the finerenone, crude (I) stage. TR (min) TRR Content and organic impurities finerenone (I) 6.2 1.00 impurity A 3.3 0.53 impurity B 3.7 0.60 impurity C 3.9 0.62 impurity D 4.4 0, 70 impurity E 5.5 0.89 impurity F 5.6 0.91 impurity G 6.8 1.10 impurity H 7.6 1.23 impurity K 10.4 1.68 impurity N 11.1 1.79 Instrument : ultra high performance liquid chromatograph (with a pressure range of up to 1200 bar with thermostatic column oven and UV detector) Column: YMC Triart C8 length: 100 mm, internal diameter: 3.0 mm, grain size: 1, 9 µm maximum pressure: 1000 bar Conditions: 20oC; 0.50 ml / min; 1.7 µl (10oC); 252 nm / 6 nm and 230 nm / 6 nm for the evaluation of dibenzoyl tartaric acid Eluting agent: A: 0.1% TFA in water; B: acetonitrile Gradient: time (min) A (%) B (%) 0.0 90.0 10.0

15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 Enantiomeric purity: TR (min) TRR Method A finerenone (I) about 11 1.00 (Ia) about 9 0.82 Equipment: high performance liquid chromatograph with thermostatic column shape and UV detector Column: Chiralpak IA length: 250 mm, internal diameter: 4.6 mm, grain size: 3.0 µm pressure maximum: 300 bar Conditions: 40oC; 0.8 ml / min; 5 µl (20oC); 255 nm / 6 nm Eluting agent: A: acetonitrile; B: methyl tert-butyl ether (MTBE) Isocratic: A (%) 90: B (%) 10 Enantiomeric purity: TR (min) TRR Method B finerenone (I) 5.7 1.00 (Ia) 6.8 1.19 Equipment / detector: high performance liquid chromatograph with thermostatic column oven, UV detector and data evaluation system Measured wavelength 252 nm: Oven temperature: 40oC Column: Chiralpak IC Length: 150 mm, internal diameter : 4.6 mm, grain size: 3 µm Mobile phase: A: 50% 20 mM ammonium acetate buffer pH 9 B: 50% acetonitrile

Flow rate: 1 ml / min Elution time: 8 minutes Equilibrium: not necessary, isocratic Sample solvent: mobile phase Test solution: dissolve about 0.5 mg / ml of the racemate substance with sample solvent Comparative solution: a comparative solution is prepared in a similar way to the test solution Injection volume: 10 µl

[0067] The measured values indicated in the examples below for the determination of the enantiomer were all determined according to method B. Some values, mainly the mixtures prepared in the pilot installation, were again measured for comparison and provided comparable results.

[0068] The HPLC analysis data indicated in the examples below in relation to purity and content for the final product finerenone, pure (I), refer only to impurities, which are present in the product with> 0.05%. This is essentially impurity E. All other impurities, which are shown in the table listed above, are, as a rule, <0.05%. The structure of these impurities was determined through the isolation of the enriched mother liquors. Example 1 Laboratory preparation using anhydrous (+) - O, O-dibenzoyl-D-tartaric acid Example 1 Preparation of tartrate (IV) salt

[0069] 250 g (660.616 mmol) of the finerenone racemate (II) were previously introduced in 3500 ml of a mixture, consisting of ethanol, denatured toluene / water = 75:25 (v / v), at room temperature (about 23oC). 130.2 g (363.339 mmol) were added

(+) - O, O-dibenzoyl-D-tartaric acid (III) through a solid funnel and then the mixture was post-washed with 250 ml of a mixture, consisting of ethanol, denatured toluene / water = 75:25 (v / v). The suspension thus obtained was heated within 0.75 hours to an internal temperature of 75oC and then it was again stirred for 3.0 hours at that temperature.

Then, within 5.0 hours the mixture was cooled on a cooling ramp from 23oC and subsequently stirred at that temperature overnight (about 16 hours). The suspension was filtered through a frit and post-washed once with 250 ml of a mixture, consisting of ethanol, denatured toluene / water = 75:25 (v / v). Wet yield: 334.7 g.

The wet product was then dried overnight (about 16 hours) at 50 ° C under vacuum (<100 mbar). Yield: 250.2 g (100.08% of theory) of a colorless crystalline powder.

Analytical results: finerenone (I) 47.2% by weight (HPLC) enantiomeric excess 97.68% e.e. largest secondary component found- 0.47% known at room temperature 5.606 minutes residual solvent: EtOH 2.24% toluene 0.0% MS (EIpos): m / z = 379 [M + H] + 1H NMR (400 MHz , DMSO-d6):  = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.39 (s, 1H), 5.89 (s, 2H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.61 (t, 4H), 7.69 (s, 1H), 7.75 (t, 2H) , 8.04 (d, 4H), 12.50-15.40 (very wide signal, 2H) and DMSO solvent signal and increased water signal:  = 2.5-2.6, as well as small peaks at  = 3.40 - 3.50 (q) and  = 1.05 - 1.10 (t), overlapping signs of residual ethanol solvent.

[0070] The colorless crystalline powder (finerenone-acid (+) - O, O-dibenzoyl-D-tartaric (VI) complex), which was obtained according to example 1a, was investigated by means of XRPD in the following conditions, at 25oC: Sample preparation: The powder is prepared as a final layer between two films (for example, polyacetate) instrument: X-ray diffractometer (powder) X'Pert Pro generator: 40 kV / 40 mA detector: PIXcel radiation: CuKa radiation wavelength: 1.5406 Å technique: transmission scanning range: 2nd £ 2Q £ 40 ° step width: 0.013o 2Q measurement time: 25 sec / step

[0071] The results are shown in Figure 1 and Table 1. Table 1: position in position in position in position 1 7,1576 18 18,3972 35 25,6188 52 31,8820 2 8,3525 19 18,8961 36 25.7895 53 322890 3 8.6020 20 19.2638 37 25.9996 54 32.6173 4 11,2018 21 20.3404 38 26.3410 55 32.9586 5 11.7664 22 20.6556 39 27.0106 56 34 , 5343 6 12.5279 23 20.9182 40 27.8510 57 35.7291 7 13.6703 24 21.6141 41 28.0873 58 36.6614 8 13.9066 25 22.0474 42 28.3237 59 37.7381 9 14.3399 26 22.2049 43 28.5863 60 38.1976 10 14.5631 27 22.5332 44 28.8620 61 38.7228 11 14.7863 28 22.8221 45 29.2034 62 39.6026 12 14.9702 29 23 , 2554 46 29,4003 in position in position in position in position 13 16.1650 30 23.6361 47 29.7942 14 16.3488 31 24.0300 48 30.0306 15 16.7427 32 24.5947 49 30.1356 16 17.25 33 24.8179 50 30.5164 17 17.4912 34 25.2118 51 30.9497 Example 1b Preparation of the crude product (I)

[0072] 248 g of compound (IV) prepared in example 1a were suspended, at room temperature, in 2480 ml of a mixture, consisting of ethanol, denatured toluene / water = 20:80 (v / v) (a pH value of pH = 4). Then, 819.6 g of an aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) were added by dripping within 60 minutes and the pH value was adjusted to pH = 7.2. The mixture was stirred continuously for 50 minutes at 23oC (pH = 7.1). Then, 98.3 g of an aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) were added by dripping within 10 minutes and the pH value was adjusted to pH = 7 , 5. The mixture was heated within an hour to an internal temperature of 50oC and again stirred for 3.0 hours at that temperature. Within an hour the mixture was cooled to 22oC and again stirred for an hour at that temperature. The crystallized product was filtered through a frit and again washed once with 100 ml of a mixture, consisting of ethanol, denatured toluene / water = 20:80 (v / v) and twice with 200 g of water. Wet yield: 263.4 g. The crude product was then dried over the weekend (> 48 hours) at 50oC under vacuum (<100 mbar). Yield: 116.9 g (93.52% of theory) of a colorless crystalline powder. Analytical results:

finerenone (I) purity: 99.86% area (HPLC) content: 100.0% by weight enantiomeric excess 97.02% e.e. largest impurity component E 0.07% residual solvent: EtOH 0.19% toluene 0.13% water (Karl-Fischer) 0.042% MS (EIpos): m / z = 379 [M + H] + 1H NMR ( 400 MHz, DMSO-d6):  = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99- 4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad sign), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and DMSO solvent signal and significantly increased water signal: δ = 2.5-2.6 , as well as a very small peak at δ = 3.38 (not attributable). Example 1c Preparation of the pure product (I)

[0073] 116.0 g of the crude product (I) prepared in example 1b were suspended in 2330 ml of ethanol, denatured toluene and then heated to reflux. In this case, the product went into solution. It was stirred again for an hour at that temperature. The solution was filtered through a heated pressure filter (T = 75oC), the pressure filter was then rinsed with 30 ml of ethanol, denatured toluene. Then, the solvent was distilled to the point (about 1920 ml was distilled) to obtain a final volume about 4 times greater (in relation to the substance used: 116 g x 4 ~ 484 ml). Then, the mixture was cooled to an internal temperature of 23oC (duration of about 1.5 to 2 hours). Then, the product was stirred for 2 hours at an internal temperature of 3 ° C. The product was filtered and washed again with 100 ml of ethanol, denatured toluene. Wet yield: 124 g. The wet product was dried at 50oC during the weekend (> 48 hours) under vacuum (<100 mbar). Yield: 112.6 g (97.07% of theory) of a colorless crystalline powder, fine needle crystals. Analytical results: finerenone (I) purity: 99.86% area (HPLC) content: 99.5% by weight enantiomeric excess 100% e.e. largest impurity component E 0.07% residual solvent: EtOH 0.05% toluene 0.00% water (Karl-Fischer) 0.00% MS (EIpos): m / z = 379 [<+ H] + NMR- 1H (400 MHz, DMSO-d6):  = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3, 99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 ( dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signs of the DMSO solvent and water at  = 2.5-2.6, as well as a very small peak at  = 3.38 (not attributable). Modification: Mod A (according to the definition in WO2016 / 016287 A1, in which the absolute configuration was determined by means of X-rays). Example 2 Laboratory preparation using (+) - O, O-dibenzoyl-D-tartaric (III) hydrate Example 2a Preparation of tartrate

[0074] 350.0 g of racemate (II) were previously introduced at room temperature and then 3112 g of water were added. Then, 1200 g of water were added. 191.4 g of acid (+) - O, O-dibenzoyl-D-tartaric (III) monohydrate were added through a solid funnel and then rinsed with

113 g of water. The suspension was heated within an hour to an internal temperature of 75oC and then stirred for 3 hours at 75oC. Then, within 5.0 hours, the suspension was cooled through a cooling ramp from 23oC and stirred again overnight (about 18 hours) at that temperature. The suspension was filtered through a frit and again washed twice with a mixture, consisting of 332.3 g of brandy and 140.2 g of water. Wet yield: 487.6 g. The wet product was then dried over the weekend (> 48 hours) at 50oC under vacuum (<100 mbar). Yield: 351.0 g (100.29% of theory) of a colorless crystalline powder. finerenone (I) content: 47.92% by weight enantiomeric excess 97.84% e.e. largest impurity component at 0.22% at room temperature 5.86 minutes residual solvent: EtOH 2.594 %% toluene 0.003%

[0075] In a similar manner, as described in example 1b and 1c, pure finerenone (I) can be prepared from that tartar salt. Example 3 Preparation of 3 mixtures of pure finerenone (I) in the technical laboratory, starting from 2 kg of racemate (II). Example 3 Preparation of tartrate (IV)

[0076] 2.00 kg (5.285 mol) of racemic finerenone (II) were previously introduced in 28.0 liters of a mixture, consisting of ethanol, denatured toluene / water = 75:25 (v / v), at room temperature (about 23oC). 1.042 kg (2.907 mol) of (+) - O, O-dibenzoyl-D-tartaric acid (III) were added through a funnel of solids and de-

because rinsed with 2 liters of a mixture, which consists of ethanol, denatured toluene / water = 75:25 (v / v). The suspension thus obtained was heated within 45 minutes to an internal temperature of 75oC and then stirred again for 3.0 hours at that temperature. Then, within 5.0 hours, the suspension was cooled through a cooling ramp from 23oC and stirred again overnight (about 16 hours) at that temperature. The suspension was filtered through a frit and again washed once with 2 liters of a mixture, consisting of ethanol, denatured toluene / water 75:25 (v / v) and aspirated dry for 10 minutes. Wet yield: 2.69 kg. The wet product was then dried at 50oC under vacuum (<100 mbar) until the dough remains constant (after about 17 hours the dough is constant). Yield: 2.009 kg (~ 1009% of theory) of a colorless crystalline powder. Example 3b Preparation of the crude product (I)

[0077] 2.006 kg of compound (IV) prepared in example 3a were suspended at room temperature (about 23oC) in 20.0 liters of a mixture, consisting of ethanol, denatured toluene / water = 1: 4 (v / v ) (a pH value of pH = 4 was measured). Then 6.05 kg of a 9.09% aqueous solution of sodium phosphate was added by dripping and the pH value was adjusted to pH = 7.2. The mixture was again stirred for about 50 minutes at 23oC (pH = 7.17). Then, 0.65 kg of a 9.09% aqueous solution of sodium phosphate was added by dripping and the pH value was adjusted to pH = 7.5. Within an hour the mixture was heated to an internal temperature of 50oC and again stirred for 3.0 hours at that temperature. Within an hour the mixture was cooled to 22oC and stirred again over the weekend (about 64 hours *) at that temperature. The crystallisate is filtered through a Seitz K800 filter plate and

washed once with 1.6 liters and once with 0.8 liters of a mixture, consisting of ethanol, denatured toluene / water = 20:80 (v / v) and twice with 1.6 liters each of water . Wet yield: 1.82 kg. The wet product was then dried at 50oC under vacuum (<100 mbar) until the dough remains constant (after about 17 hours the dough is constant). Yield: 0.978 kg (97.8% of theory) of a colorless crystalline powder. *) for technical reasons, it was again agitated during the end of the week, as a rule, just 14 hours of time for another agitation. Example 3c Preparation of the pure product (I)

[0078] 250 g of the crude product (I) prepared in example 3b were suspended in 5000 ml of ethanol, denatured toluene and then heated to reflux. In this case, the product went into solution. It was stirred again for an hour at that temperature. The solution was filtered through a heated pressure filter (T = 85oC), the pressure filter was then rinsed with 200 ml of ethanol, denatured toluene. Then, the solvent was distilled to the point (about 4200 ml was distilled) until a final volume about 4 times higher (in relation to the substance used: 250 g x 4 ~ 1000 ml). Then, the mixture was cooled to an internal temperature of 4-5oC (ramp: duration of about 4 hours). Then, it was stirred for 1 hour at an internal temperature of 4-5oC. The product was filtered and washed again with 200 ml of ethanol, denatured toluene. Wet yield: 251.2 g. The wet product was dried at 50oC during the weekend (> 48 hours) under vacuum (<100 mbar). Yield: 223.0 g (89.2% of theory) of a colorless crystalline powder.

[0079] Table 4 below summarizes the results of 3 campaigns starting with 2 kg of finerenone (II) racemate, respectively:

Table 4: Salt of tartrate (IV) preparation racemate (II) yield: yield: used kg% of theory preparation 1 (example 3a) 2 2,009 ~ 100 preparation 2 2 2,025 ~ 100 preparation 3 2 2,027 ~ 100 preparation content (I) % purity (HPLC) excess solvent re- enantiomeric weight rich ee % preparation 1 49.20 largest compound 97.69 ethanol: (example 3a) secondary to temperature- 2.55% ambient temperature no: 0.01% 5.606 min: 0.22% preparation 2 49.80 largest compound 97 , 49 ethanol: secondary to tem- 2.74% ambient temperature no: 0.00% 5.606 min: 0.11% preparation 3 50.06 largest compound 97.64 ethanol: secondary to tem- 2.58% tolue - ambient temperature no: 0.004% 5.606 min: 0.14% Crude product (I) preparation of tartrate salt yield: yield: used (IV): kg kg% of theory preparation 1 (example 3b) 2.009 0.978 97.8 preparation 2 2.025 0.985 98.5 preparation 3 2.027 0.987 98.7 preparation content (I)% purity (HPLC) excess solvent re- enantiomeric weight rich ee % preparation 1 98.10 finerenone (I): 98.15 ethanol: (example 3a) 99.85% 0.203% toluene: 0.117% preparation 2 99.00 finerenone (I): 97.93 ethanol: 99.83% higher 0.110% sec-toluene compound: dary impurity E: 0.073% 0.08% preparation 3 99.70 finerenone (I): 97.97 ethanol: 99.84% higher 0.118% sec-toluene compound: dary impurity E: 0.076 0 , 07% In all 3 preparations, the content of (+) - O, O-dibenzoyl-D-tartaric acid was: 0.00%. Pure product (I) preparation crude product yield: g yield: (I)% of theory preparation 1 (example 3c) 250 223 89.2 preparation 2 250 235 94.0 preparation 3 250 226 91.8 preparation content (I) purity (HPLC) residual solvent excess% in rich enantiomer- ee % preparation 1 99.40 finerenone (I): 100.00 ethanol: 0.074% (example 3a) 99.82% toluene: 0.000% impurity E 0.08%

preparation (I) purity (HPLC) excess residual solvent% in rich enantiomer e.e. % preparation 2 99.80 finerenone (I): 100.00 ethanol: 0.037% 99.94% toluene: 0.000% impurity E: 0.08% preparation 3 99.50 finerenone (I): 99.92 ethanol: 0.033% 99.85% toluene: 0.000% impurity E: 0.08% In all 3 preparations, the content of (+) - O, O-dibenzoyl-D-tartaric (III) was 0.00%. Example 4

[0080] Industrial realization of the process. The examples below describe the process reaction on an industrial scale. The results, such as yield and analytical data for 2 mixtures of pure finerenone (I) are shown below in tables: Example 4a Preparation of the tartrate salt (IV)

[0081] The size of the mixture corresponded to 80 kg of racemic finerenone (II). ● In a 1600 liter shaker, at an internal temperature of 20oC, 711.0 kg of brandy were previously introduced, then 300 kg of water were added, then 80.0 kg of raccoon (II) and finally, 41.7 kg of (+) - O, O-dibenzoyl-tartaric acid (III). ● The mixture was heated to an internal temperature of 75oC and stirred again for 3 hours. ● The mixture was cooled for 5 hours (ramp) to an internal temperature of 23oC and again stirred for 16 hours. ● For centrifugation, the suspension was transferred to an inversion centrifuge, centrifuged and washed again with a mixture, consisting of 10.7 kg of brandy and 4.5 kg of water, then dried by centrifugation and removed. ● Drying took place in a 300 liter spherical dryer at a jacket temperature of 50oC and 30 mbar. The drying was interrupted at an internal temperature of 45oC (about 6 hours). ● The product was cooled to 15oC and then removed. Example 4b Crude product (I)

[0082] The size of the preparation corresponded to 89.3 kg of tartrate (IV) salt for use. ● Preparation of a sodium phosphate solution ● In a 630 liter shaker, at 20oC, 360.0 kg of demineralized water were previously introduced. ● 36.0 kg of sodium phosphate were added and dissolved ● In a 1600 liter stirrer, at 20oC, 141.1 kg of brandy were previously introduced. ● Then 714.2 kg of water and 89.3 kg of tartrate salt (IV) were added. ● The mixture was heated to an internal temperature of 50oC. ● Then, 295.1 kg of a sodium phosphate solution were added. ● After 1.5 hours, the pH value was adjusted to pH = 7.5 (+/- 0.1) by adding 35.4 kg of sodium phosphate solution ● The mixture was left to stir again and cooled through a ramp (3 hours) to the internal temperature = 22oC. ● Then, it was again stirred at room temperature = 22oC (18 hours)

● In a container a mixture of 129.6 kg of water and 25.6 kg of brandy was prepared (to wash again) ● The suspension was dosed in the inversion centrifuge (about 4 loads + remaining load) and washed in portions one once with a mixture of 129.6 kg of water and 25.6 kg of brandy and once with 288.0 kg of demineralized water. ● The product was removed and dried in the spherical dryer (jacket temperature = 50oC, 30 mbar, completed at internal temperature = 45oC, about 6 hours). ● The product was cooled and removed to <30oC. Example 4c Reprocessing the crude product (I)

[0083] In some cases, if the specification limit value for (+) - dibenzoyl-tartaric acid (III) in the crude product is> 0.1%, it is found to be advantageous to carry out a reprocessing (see example - example 6), which guarantees that the limit value of <0.1% is reproducibly obtained. The reprocessing process, moreover, is almost loss-free and provides the crude product, as a rule, at a yield of> 95%. Crude product (I) reprocessed

[0084] The size of the preparation corresponded to 30 kg of crude product (I). ● Preparation of a sodium phosphate solution: 2.3 kg of sodium phosphate were dissolved, at room temperature, in 147.8 kg of water in a 250 liter stirring vessel. ● At 20C, in a 630 liter agitator, 198.8 kg of water were previously introduced and 120 kg of water were added, then 30 kg of crude product (containing (+) - dibenzoyl- tartaric acid (III), as indicated in table 5). ● The mixture was heated to an internal temperature of 70oC and again stirred for 30 minutes. ● at 70oC, 14.1 kg of the sodium phosphate solution prepared above was dosed and a pH value of pH of 8.9 (+/- 0.1) and the mixture was again stirred for 20 hours at 70oC. ● Using a ramp, within 60 minutes, this was cooled to 44oC and 300 g of pure fine-renone vaccination crystals (I) were added. ● Then, at 200 mbar and a maximum internal temperature of 60oC, it was distilled and in parallel 369 kg of water were dosed in the shaker. ● Finally, within 1.5 hours, the mixture was cooled to 22oC and the product was isolated in a pressurized suction filter and washed in 3 portions with a total of 180 liters of water. ● Then, the product was dried at 50 ° C under vacuum (30 mbar) until weight constant. ● It was allowed to dry at 15oC and the product was removed. Example 4d Gross product (I)

[0085] The size of the preparation corresponded to 26 kg (2 times 13 kg) of crude product (I) reprocessed. ● In a 250 liter agitator, 13 kg of reprocessed crude product (I) were previously introduced with 184.9 kg of water at 20oC and the agitator was previously inertized. ● The solution was heated to a jacket temperature of 80oC and again stirred for 30 minutes at 78oC (in this case, the product goes into solution). ● The solution was filtered through a 0.65 µm filter plug (PP Sartorius plug) (GMP filtration) and the filtrate was transferred to a 630 liter agitator. ● The filtrate was washed again with 18.5 kg of water

you. ● This was repeated in 2 partial portions (2 times 13 kg of product) and the solutions were combined. ● At a final filling level of about 130 liters, normal pressure was distilled (in two portions, jacket temperature: 104oC, duration of about 6 hours). ● The solution was cooled by means of a linear temperature ramp for 4 hours at 0oC and then it was again stirred for an hour. ● The product suspension was isolated through a pressurized suction filter and washed with 45.9 kg of brandy. ● The wet product was then dried under vacuum (30 mbar) at 50oC until weight constant (about 12 hours). It was cooled to 15 ° C and the product was removed.

[0086] A summary of the yield and analytical results of 3 industrial preparations for the preparation of pure finerenone (I) is shown in table 5. Tartrate salt (IV) Table 5: racemate preparation (II) yield yield:% of used kg of tartrate salt theory (non-corri- (IV): kg for content) preparation 1 80 77.3 100 (example 4a) preparation 2 80 81.2 105 preparation 3 80 80.2 103 preparation salt content of fine-purity (HPLC) content tartrate (IV) renone (I) enantiomer-% by weight% by weight rich ee % preparation 1 94.2 48.4 (+) - 98.6 (example 4a) dibenzoyl-tartaric: 44.98% preparation 2 95.4 49.0 (+) - 98.6 dibenzoyl-tartaric: 44 , 98% preparation 3 94.2 48.4 acid (+) - 98.6 dibenzoyl-tartaric: 44.98% Crude product (I) preparation tartrate salt yield (I, yield:% of (IV) used) crude ): kg theory preparation 1 89.3 36.6 80 (example 4b) preparation 2 89.3 44.2 96 preparation 3 89.3 45.7 99 preparation content (I) purity (HPLC) excess solvent re% in enantio- sidual weight and ee % preparation 1 98.5 finerenone (I): 99.71% 98.8 ethanol: (example 4b) impurity E: 0.08% so- 0.098% ma of all compo- toluene: secondary components or- 0.048% organic : 0.29% (+) - dibenzoyl-tartaric acid: 0.71%

preparation 2 98.2 finerenone (I): 97.7% 98.9 ethanol: impurity E: 0.08% 0.151% sum of all com- toluene: secondary components 0.088% organic: 0.30% acid (+) -dibenzoyl-tartaric: 0.39% preparation 3 100 finerenone (I): 99.76% 98.7 ethanol: impurity E: 0.07% only- 0.102% ma of all compounds: secondary components or- 0.066 % gamic: 0.24% acid (+) - dibenzoyl-tartaric: 0.46%

Crude product (I) after reprocessing preparation use (I): kg yield yield:% (I): kg by weight preparation 1 (example 4c) 30 29.8 99.33 preparation 2 30 29.8 99.33 preparation content (I) purity (HPLC) excess solvent% in residual enantiomer- rich weight ee % preparation 1 99.6 finerenone (I): 99.70% 98.8 ethanol: n.n. (example 4c) (+) - dibenzoyl-toluene: tartaric acid: <0.05% n.n. largest secondary component impurity E: 0.08% sum of all secondary organic components: 0.3%

preparation 2 99.6 finerenone (I): 99.70% 98.8 ethanol: n.n. (+) - dibenzoyl-toluene: tartaric acid: <0.05% n.n. largest secondary component impurity E: 0.08% sum of all organic secondary components: 0.3% Pure product, pure finerenone (I) preparation use kg yield: yield: kg% by weight preparation 1 (example 4d ) 26 23.1 88.85 preparation 2 26 22.9 88.08 preparation content (I) purity (HPLC) excess solvent% enantiomer- residual rich weight ee % preparation 1 100 finerenone (I): 99.8% 100 ethanol: (example 4d) sum of all 0.044 secondary tolu-components: 0.00 organic diaries: 0.2% water: <0.2 largest component secondary impurity E: 0.08% acid (+) - dibenzoyl-tartaric: <0.05 preparation 2 100 finerenone (I): 99.8% 100 ethanol: sum of all 0.063 secondary components: 0.00 organic diaries: 0.2% water: <0.2 largest secondary component impurity E: 0.08% acid (+) - dibenzoyl-tartaric: <0.05

Example 5

[0087] For the release of crude finerenone (I), several variants similar to the instruction in example 1b are suitable. The objective, in this case, was to keep the proportion of (+) - O, O-dibenzoyl-D-tartaric (III) in the crude product as low as possible (0.15% and below). In this case, individually, the final pH value varied after the dosage of the sodium phosphate solution, temperature, time of addition of the sodium phosphate solution and time of another stirring and the influence on the acid content ( +) - O, O-dibenzoyl-D-tartaric was investigated in the crude product.

[0088] Size of the preparation: 100 g of tartrate salt (IV) in 158.0 g of brandy and 779.8 g of water

[0089] Analytical data for the tartrate (IV) salt used: finerenone (I) 48.05% by weight (HPLC) enantiomeric excess 97.71% e.e. largest secondary component unknown - 0.28% acid at room temperature 5.606 min. residual solvent: EtOH 2.576% toluene 0.006%

[0090] The following table summarizes the results: Table 6 pre-pH amount T (° C) time purity time ratio proportion of Na3PO4 acid fine stirring solution additional strain (+ ) - (100 g / 1 (min.) (Min.) (I) (% of dibenzoyl-liter of HPLC theory) tartaric (% water (%) by weight) 1 7.5 400 50 30 180 99.17 97 , 2 0.0996 2 7.5 400 60 30 180 99.74 97.2 0.1101 3 8.0 444.9 50 30 180 99.86 97.0 0.0986 4 8.5 467.7 50 30 180 99.73 96.6 0 , 1298 5 9.0 480.3 50 30 180 99.85 97.4 0.1027 prep- pH amount T (° C) time purity time ratio of fine-di- stirring solution Na3PO4 additional sizing (+) - (100 g / 1 (min.) (Min.) (I) (% of dibenzoyl-liter of HPLC theory) tartaric (% water (%) by weight) 6 7.5 400 50 30 60 99.86 96.8 0.1010 7 7.5 400 50 30 300 99.87 97.2 0.1058 8 7.5 400 50 8 180 99.73 97.6 0.1294 Example 6 Process of reprocessing Example 6a Reprocessed crude product: Reduction in the proportion of acid (+) - O, O - dibenzoyl-D-tartaric <0.1%

[0091] This experiment served to demonstrate the robustness of the reprocessing process, in which a load with an increased proportion of (+) - O, O-dibenzoyl-D-tartaric acid (III) was consciously used.

[0092] A crude product which, according to the analysis, still contained 0.77% acid (+) - O, O-dibenzoyl-D-tartaric (III), was used for reprocessing. crude finerenone (I) purity: 99.67% area (HPLC): content: 98.69% acid weight (+) - O, O-dibenzoyl-D-tartaric 0.77% higher secondary component impurity E 0, 07% Crude product reprocessing: Reduced proportion of (+) - O, O-dibenzoyl-D-tartaric acid (III) <0.1%

[0093] A crude product that, according to the analysis, still contains 0.77% of acid (+) - O, O-dibenzoyl-D-tartaric (III), was used for reprocessing. Here it was processed as follows:

[0094] 150 g of crude product (I) (containing, 77% (+) - O, O-dibenzoyl-D-tartaric acid (III)) were added to 600 g of water and 953.9 g of brandy and heated to 70oC. Within an hour, everything was resolved. Then, the mixture was again stirred for 30 minutes at 70oC. The pH value is pH = 5.0. The pH value was adjusted to pH = 8.5 by adding 44.6 g of an aqueous solution of sodium phosphate (15 g of sodium phosphate to 985 g of water) and then the mixture was stirred for 2 hours at 70oC. Within 30 minutes, the mixture was cooled to 53oC and inoculated with pure material (inoculation crystals). Then it was again stirred for 30 minutes at 50-52oC. At 200 to 155 mbar and at an internal temperature, ethanol was almost completely distilled and in parallel 1845 ml of water was added (the filling level was kept constant: from the distilled amount = amount of water added). The heating was turned off and the suspension was again stirred overnight at 23oC. The crystallize was filtered through a frit and washed three times with 300 ml each of water. Wet yield: 218.9 g. The wet product was dried at 50oC during the weekend (> 48 hours) in a vacuum (<100 mbar). Yield: 146.7 g (97.8% of theory). finerenone (I) purity: 99.87 area (HPLC); content: 100.3% by weight enantiomeric excess 97.87% e.e. (+) - O, O-dibenzoyl-D- 0.00% tartaric major secondary component 0.07% impurity AND residual solvent: EtOH 0.286% Example 6b Demonstration of stability, agitation for 20 hours at 70oC Reprocessing of the crude product: Reduction in the proportion of (+) - O, O-dibenzoyl-D-tartaric acid (III) <0.1%

[0095] A crude product, which according to the analysis still contains 0.77% of acid (+) - O, O-dibenzoyl-D-tartaric (III), was used for the recovery

processing. To that end, it was processed as follows:

[0096] 150 g of crude product (I) (containing, 77% (+) - O, O-dibenzoyl-D-tartaric acid (III)) were added to 600 g of water and 953.9 g of brandy and again stirred at 70oC. Within an hour, everything was resolved. Then, the mixture is stirred again for 30 minutes at 70oC. The pH value is pH = 5.0. The pH value was adjusted to pH = 8.5 by adding 45.2 g of an aqueous sodium phosphate solution (15 g of sodium phosphate to 985 g of water) and then the mixture was stirred for 20 hours at 70oC. Within 30 minutes, the mixture was cooled to 53oC and inoculated with pure material (inoculation crystals). Then, it was stirred again for 30 minutes at 50-52oC. At 200 to 155 mbar and at an internal temperature, ethanol was almost completely distilled and in parallel 1845 ml of water was added (the filling level was kept constant: from the distilled quantity = amount of water added ). The heating was turned off and the suspension was again stirred overnight at 23oC. The crystallize was filtered through a frit and washed three times with 300 ml each of water. Wet yield: 194.3 g. The wet product was dried at 50oC overnight (about 16 hours) in a vacuum (<100 mbar). Yield: 143.1 g (95.4% of theory). finerenone (I) purity: 99.86 area (HPLC); content: 101.3% by weight enantiomeric excess 97.85% e.e. (+) - O, O-dibenzoyl-D- 0.00% area (0.024% by weight) tartaric major secondary component 0.07% impurity AND residual solvent: EtOH 0.128% Example 6 c Reprocessing of the crude product: Reduction of the proportion of (+) - O, O-dibenzoyl-D-tartaric acid (III) <0.1%. Retitulation of the pH value to pH 7.0 with sodium dihydrogen phosphate

[0097] A crude product, which according to the analysis still contains 0.77% acid (+) - O, O-dibenzoyl-D-tartaric (III), was used for reprocessing. To that end, it was processed as follows:

[0098] 375.0 g of crude product (I) (containing 0.77% acid (+) - O, O-dibenzoyl-D-tartaric (III)), were added to 1500 g of water and 2384.8 g of brandy and heated to 70oC. Within an hour, everything was resolved. Then, it is stirred again for 30 minutes at 70oC. The pH value is pH = 4.9. The pH value was adjusted to pH = 8.5 by adding 101.4 g of an aqueous sodium phosphate solution (15 g of sodium phosphate to 985 g of water) and then stirring for 20 hours at 70oC. Then, the pH value was adjusted to pH = 7 with a solution of sodium dihydrogen phosphate (50 g of sodium dihydrogen phosphate in 200 ml of water). Within 30 minutes, it was cooled to 53oC and inoculated with pure material (inoculation crystals). Then it was again stirred for 30 minutes at 50-52oC. At 200 to 155 mbar and at an internal temperature, ethanol was almost completely distilled and in parallel, 4610 ml of water was added (the filling level was kept constant: from the distilled quantity = quantity of water added). Then, within 90 minutes, the mixture was cooled to 23oC. Then it was stirred again over the weekend (about 70 hours) at 22oC. The crystallize was filtered through a frit and washed three times with 750 ml each of water. Wet yield: 402.3 g. The wet product was dried at 50oC overnight (about 16 hours) in a vacuum (<100 mbar). Yield: 336.6 g (89.76% of theory). finerenone (I) purity: 99.84 area (HPLC); content: 99.2% by weight enantiomeric excess 98.02% e.e. (+) - O, O-dibenzoyl-D-tartaric 0.00% area (0.0068% by weight)

major secondary component impure - 0.07% za E residual solvent: EtOH 0.107% toluene 0.001% Example 6d Final crystallization of the preparation of example 6c

[0099] 80.0 of the crude product (I) prepared in example 6c were suspended in 1600 ml of ethanol, denatured toluene and then heated to reflux. The solution, in this case, came into solution. It was stirred again for an hour at that temperature. The solution was filtered through a pressurized heated suction filter (T = 75oC), then rinsed with 100 ml of ethanol, toluene. Then, the solvent was distilled in a vacuum (jacket temperature 45-47oC) as moderately as possible, until a final volume about 5 times higher (in relation to the substance used: 80 g x 5 ~ 400 ml) was obtained. Then, within an hour, the mixture was cooled to an internal temperature of 2oC and stirred for about 1 hour at that temperature. The product was filtered and washed again with 80 ml of ethanol, denatured toluene. Wet yield: 83.3 g. The wet product was dried at 50oC overnight (about 16 hours) under vacuum (<100 mbar). Yield: 71.4 g (89.3% of theory) of a colorless crystalline powder, fine acicular crystals. finerenone (I) purity: 99.82 area (HPLC); content: 98.7% by weight enantiomeric excess 99.87% e.e. major secondary component impure- 0.07% za E residual solvent: EtOH 0.489% toluene 0.005% Example 7

Isolation of the finerenone enantiomer (Ia) Example 7a Preparation of the salt of (-) - O, O-dibenzoyl-L-tartaric acid

[00100] 187.2 g of racemate (II) were previously introduced at room temperature and then 1662.5 g of brandy were added. Then, 485.5 g of water were added. 97.5 g of (-) - O, O-dibenzoyl-L-tartaric acid (IIIa) were added through a solid funnel and then rinsed again with 156.0 g of water. The suspension was heated within an hour to an internal temperature of 75oC and then it was stirred for 3 hours at 75oC. Then, within 5.0 hours, the mixture was cooled through a cooling ramp from 23oC and stirred again overnight (about 18 hours) at that temperature. The suspension was filtered through a frit and again washed twice with a mixture, consisting of 178 g of brandy and 75 g of water. Wet yield: 255.4 g. The wet product was then dried overnight (about 16 hours) at 50oC under vacuum (<100 mbar). Yield: 188.6 g (100.73% of theory) of a colorless crystalline powder. The mother liquor and the washing solution were combined (about 3200 ml of yellowish solution, pH = 4.6) and from there, the finerenone was crude isolated (I) (example 7b). finerenone (Ia) 49.3% by weight (HPLC) enantiomeric excess 97.35% e.e. residual solvent: EtOH 1.847% toluene 0.00%

In a similar manner, as described in example 1b and 1c, the finerenone enantiomer (Ia) can be prepared from that tartrate salt. Example 7b Isolation of finerenone, crude (I) from the mother liquor

[00102] The combined mother liquor and the washing solution of example 7a (about 3200 ml of yellowish solution, pH = 4.6) were adjusted to pH = 7.6, at room temperature, through addition of 43.3 g of an aqueous solution of sodium phosphate (100 g dissolved in 1 liter of water). Then, under reduced pressure (85 to 65 mbar, internal temperature from 38 to 20oC), the brandy was widely distilled and reduced to a final volume of about 0.8 liters. The mixture was cooled to room temperature and the precipitated suspension was stirred for 2 hours at 22oC. The suspension was filtered and washed twice with 150 ml of water each. Wet yield: 159.1 g. The wet product was dried at 50oC overnight (about 16 hours) under vacuum (<100 mbar). Yield: 86.3 g (92.2% of theory based on the racemate used in example 7a (II)). finerenone (I) purity: 99.48 area (HPLC); content: 99.39% by weight enantiomeric excess 99.14% e.e. largest secondary component impu 0.13% with E acid (-) - O, O-dibenzoyl-L-tartaric 0.14% (0.05% by weight)

[00103] Similarly, as described in example 1c, from that crude product finerenone (I) can be produced in pure form. Example 8 Example 8a Isolation of the wrong enantiomer (Ia) from the mother liquor

[00104] The combined mother liquor and the washing solution of example 1a (about 3750 ml of yellowish solution, pH = 4.5) were adjusted to pH = 7.5, at room temperature, through addition of 101.1 g of an aqueous sodium phosphate solution (100 g dissolved in 1 liter of water). Then, under reduced pressure (85 to 65 mbar, internal temperature of 38 to 20oC), the brandy was largely destined

reduced to a final volume of about 0.85 liters. The mixture was cooled to room temperature and the precipitated suspension was stirred over the weekend (> 48 hours), then stirred for another 2 hours at 22oC. The suspension was filtered and washed twice with 200 ml of water each. Wet yield: 139.1 g. The wet product was dried at 50oC overnight (about 16 hours) under vacuum (<100 mbar). Yield: 103.1 g (82.48% of theory based on the racemate used in example 1a (II)). finerenone (I) purity: 99.75 area (HPLC); content: 99.2% by weight enantiomeric excess 99.34% e.e. major secondary component impure- 0.12% za E acid (+) - O, O-dibenzoyl-D-tartaric 0.14% (0.05% by weight) water 0.102% Example 8b Industrial preparation for the isolation of the enantiomer of finerenone (Ia)

[00105] A combined mother liquor and washing solution of example 4 (tartrate preparation on an industrial scale) were processed as follows: amount about 1165 kg of solution ● Preparation of a sodium phosphate solution: 7, 3 kg of sodium phosphate were dissolved in 73.1 kg of water at 20oC ● In a 1600 liter shaker, 1165 kg of mother liquor (including the washing solution) were previously introduced at 20oC and adjusted to pH of 7.5 (+/- 0.1) with 28 kg of the sodium phosphate solution prepared above ● The mixture was again stirred for 0.25 hours and then under vacuum (65 mbar, internal temperature of approx. (22oC), the brandy was distilled to a filling level of about 310 liters ● Then, the mixture was again stirred for 2 hours at 20oC and the suspension was isolated through an inverting centrifuge, being washed with 20 kg of water each. ● The wet product was dried in a spherical dryer at 50oC under vacuum (30 mbar; about 6 hours) ● The mixture was cooled to 15oC and the product was removed.

[00106] Analytical data of the mother liquor used (including the washing solution) for the preparation 1 finerenone (I) 92.4% (HPLC) enantiomeric excess 95.92% e.e. major secondary component impurity E 0.26% acid (+) - O, O-dibenzoyl-D-tartaric 5.38 residual solvent ethanol 0.319% toluene 0.001%

[00107] Analytical data of the mother liquor used (including the washing solution) for the preparation 2 finerenone (I) 92.03% enantiomeric excess 99.03% e.e. major secondary component impurity E 0.15% acid (+) - O, O-dibenzoyl-D-tartaric 5.94 residual solvent ethanol 0.177% toluene 0.001% preparation kg used yield-yield: to: kg% of theory preparation 1 ~ 1165 mother liquor (including 38.2 96 washing solution) preparation 2 ~ 1165 mother liquor (including 93 washing solution)

[00108] Analytical data of preparation 1 finerenone (I) purity: 99.71% enantiomeric excess 96.56% e.e. major secondary component impurity E 0.106% acid (+) - O, O-dibenzoyl-D-tartaric 0.081

[00109] Analytical data for preparation 2 finerenone (I) purity: 99.44% enantiomeric excess 99.5% e.e. major secondary component impurity E 0.107% acid (+) - O, O-dibenzoyl-D-tartaric 0.33 Example 9 Examples of other derivatives of tartaric acid and other solvents Example 9a Acid (+) - O, O-di-p -anisoil-D-tartaric

[00110] 100 mg of racemate and 111 mg of (+) - O, O-di-p-anisoyl-D-tartaric acid were dissolved in 5 ml of dichloromethane and left to stand. After some time, the diastereomeric salt precipitated. This was filtered and the enantiomeric excess was measured. The measurement resulted in an enantiomeric excess of 68% e.e. in favor of (Ia). Example 9b (-) - O, O’-di-p-toluyl-L-tartaric acid

[00111] 100 mg of racemate and 0.55 equivalent of (-) - O, O-di-p-toluyl-L-tartaric acid were dissolved in 4 ml of solvent and left to stand. After some time, the diastereomeric salt precipitated. This was filtered and the enantiomeric excess was measured. The measurement resulted in an enantiomeric excess of y% e.e. in favor of (Ia). The following table 7 summarizes the results.

Table 7: 4 ml of solvent / mixture of enantiomeric excess e.e. % solvents (Ia) n-propanol / water 80:20 85.35 n-pentanol / water 90:10 89.10 methanol / water 80:20 84.47 methanol 93.18 isopropanol / water 80:20 81.20 isobutanol / water 90:10 79.25 ethylene glycol / water 80:20 93.68 ethylene glycol 68.50 ethanol / water 80:20 85.87 ethanol 85.96 2-butanol / water 80:20 83.92 1-butanol / water 90:10 88.93 Example 9c (+) - O, O-dibenzoyl-D-tartaric acid

[00112] 100 mg of racemate and 0.55 equivalent of (+) - O, O-di-benzoyl-D-tartaric acid were dissolved in 4 ml of solvent and left to stand. After some time, the diastereomeric salt precipitated. This was filtered and the enantiomeric excess was measured. The measurement resulted in an enantiomeric excess of y% e.e. in favor of (Ia). The following table 8 summarizes the results. Table 8: 4 ml of solvent / mixture of enantiomeric excess e.e. % (I) solvents n-propanol / water 80:20 94.01 n-pentanol / water 90:10 94.59 methanol / water 80:20 89.09 methanol 91.21 isopropanol / water 80:20 90.92

4 ml of solvent / mixture of enantiomeric excess e.e. % (I) solvents isobutanol / water 90:10 85.42 ethylglycol 92.08 ethanol / water 80:20 94.64 ethanol 93.64 cyclohexanol / water 90:10 84.33 benzyl alcohol / water 90:10 88.83 2-butanol / water 80:20 92.49 1-pentanol 80.99 1-butanol / water 90:10 94.02 Description of Figure Figure 1: XRPD of compound (VI) obtained as colorless crystalline powder according to the example 1a.

Claims (15)

1. Dissociation of the racemate from (II) (R, S-II) in (Ia) and / or (I) (Ia) (I) characterized by the fact that it is with substituted chiral tartaric acid esters of the general formulas (IIIa ) or (IIIb) (IIIa) (IIIb) in which Ar represents an unsubstituted or substituted aromatic or heteroaromatic radical. 2. Process for the preparation of (4S) -4- (4-cyano-2-methoxy-phenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox -amide of formula (I) (I) characterized by the fact that it is by dissociation of the racemate of (II) (R, S-II) with a substituted chiral tartaric acid ester of formula (IIIa) (IIIa) in which Ar represents an unsubstituted or substituted aromatic or heteroaromatic radical. 3. Process according to claim 1 or 2, characterized characterized by the fact that the racemate is dissociated in an ethanol / water mixture. 4. Process according to any one of claims 1 to 3, characterized by the fact that the dissociation of the racemate occurs at a temperature in the range of 60 to 80oC. 5. Process according to any one of claims 1 to 4, characterized by the fact that Ar represents phenyl. 6. Process according to any one of claims 1 to 5, characterized by the fact that dibenzoyltartaric acid (III) is used for the separation of the racemate. 7. Process according to any one of claims 1 to 6, characterized by the fact that it isolates the precipitated diastereomeric salt (IVa), (IVb), (IVc) and / or (IVd). 8. Process according to any one of claims 1 to 7, characterized in that it treats the diastereomeric salt with a base and removes the solvent. 9. Process according to any one of claims 1 to 8, characterized in that it uses potassium hydroxide, potassium phosphate or sodium phosphate as a base. 10. Process according to any one of claims 1 to 9, characterized by the fact that the racemate (R, S-II) is reacted with dibenzoyltartaric acid of the formula (III) in a spirit / water mixture to form the diastereomeric salt (VI) and then finerenone (I) (I) is released using sodium phosphate in the same way in a spirit / water mixture. 11. Diastereomeric salts, characterized by the fact that they present formulas (IVa) (IV-b) (IV-c) or (IV-d) in which Ar represents an unsubstituted or substituted aromatic or heteroaromatic radical. 12. Diastereomeric salt according to claim 11, characterized by the fact that Ar represents or in which * represents the connection point. 13. Diastereomeric salt according to claim 11 or 12, characterized by the fact that Ar represents phenyl. 14. Finerenone (I) with a dibenzoiltartaric acid content of <0.15%, characterized by the fact that it is obtained by the fact that the racemate (II) (II) (R, S-II) is reacted with dibenzoiltartaric acid of formula (III) in a spirit / water mixture to form the diastereomeric salt (VI) and then the finerenone (I) (I) (I) is released using sodium phosphate in the same way in a spirit / water mixture and then reacted again with sodium phosphate in a spirit / water and then the finerenone is crystallized with a content of dibenzoyltartaric acid <0.15%. 15. Finerenone (I) with a dibenzoyltartaric acid content <0.1%, characterized by the fact that it is by a process, as defined in claim 14.